The invention relates generally to methods for continually or continuously measuring the concentration of target chemical analytes present in a biological system. More particularly, the invention relates to methods for processing signals obtained during measurement of physiological analytes. One important application of the invention involves a method for monitoring blood glucose concentrations.
A number of diagnostic tests are routinely performed on humans to evaluate the amount or existence of substances present in blood or other body fluids. These diagnostic tests typically rely on physiological fluid samples removed from a subject, either using a syringe or by pricking the skin. One particular diagnostic test entails self-monitoring of blood glucose levels by diabetics.
Diabetes is a major health concern, and treatment of the more severe form of the condition, Type I (insulin-dependent) diabetes, requires one or more insulin injections per day. Insulin controls utilization of glucose or sugar in the blood and prevents hyperglycemia which, if left uncorrected, can lead to ketosis. On the other hand, improper administration of insulin therapy can result in hypoglycemic episodes, which can cause coma and death. Hyperglycemia in diabetics has been correlated with several long-term effects of diabetes, such as heart disease, atherosclerosis, blindness, stroke, hypertension and kidney failure.
The value of frequent monitoring of blood glucose as a means to avoid or at least minimize the complications of Type I diabetes is well established. Patients with Type II (non-insulin-dependent) diabetes can also benefit from blood glucose monitoring in the control of their condition by way of diet and exercise.
Conventional blood glucose monitoring methods generally require the drawing of a blood sample (e.g., by fingerprick) for each test, and a determination of the glucose level using an instrument that reads glucose concentrations by electrochemical or calorimetric methods. Type I diabetics must obtain several fingerprick blood glucose measurements each day in order to maintain tight glycemic control. However, the pain and inconvenience associated with this blood sampling, along with the fear of hypoglycemia, has led to poor patient compliance, despite strong evidence that tight control dramatically reduces long-term diabetic complications. In fact, these considerations can often lead to an abatement of the monitoring process by the diabetic. See, e.g., The Diabetes Control and Complications Trial Research Group (1993) New Engl. J. Med. 329:977-1036.
Recently, various methods for determining the concentration of blood analytes without drawing blood have been developed. For example, U.S. Pat. No. 5,267,152 to Yang et al. describes a noninvasive technique of measuring blood glucose concentration using near-IR radiation diffuse-reflection laser spectroscopy. Similar near-IR spectrometric devices are also described in U.S. Pat. No. 5,086,229 to Rosenthal et al. and U.S. Pat. No. 4,975,581 to Robinson et al.
U.S. Pat. No. 5,139,023 to Stanley et al., and U.S. Pat. No. 5,443,080 to D""Angelo et al. describe transdermal blood glucose monitoring devices that rely on a permeability enhancer (e.g., a bile salt) to facilitate transdermal movement of glucose along a concentration gradient established between interstitial fluid and a receiving medium. U.S. Pat. No. 5,036,861 to Sembrowich describes a passive glucose monitor that collects perspiration through a skin patch, where a cholinergic agent is used to stimulate perspiration secretion from the eccrine sweat gland. Similar perspiration collection devices are described in U.S. Pat. No. 5,076,273 to Schoendorfer and U.S. Pat. No. 5,140,985 to Schroeder.
In addition, U.S. Pat. No. 5,279,543 to Glikfeld et al. describes the use of iontophoresis to noninvasively sample a substance through skin into a receptacle on the skin surface. Glikfeld teaches that this sampling procedure can be coupled with a glucose-specific biosensor or glucose-specific electrodes in order to monitor blood glucose. Finally, International Publication No. WO 96/00110, published Jan. 4, 1996, describes an iontophoretic apparatus for transdermal monitoring of a target substance, wherein an iontophoretic electrode is used to move an analyte into a collection reservoir and a biosensor is used to detect the target analyte present in the reservoir.
The present invention provides a method for continually or continuously measuring the concentration of an analyte present in a biological system. The method entails continually or continuously detecting an analyte from the biological system and deriving a raw signal therefrom, wherein the raw signal is related to the analyte concentration. A number of signal processing steps are then carried out in order to convert the raw signal into an initial signal output that is indicative of an analyte amount. The converted signal is then further converted into a value indicative of the concentration of analyte present in the biological system.
The raw signal can be obtained using any suitable sensing methodology including, for example, methods which rely on direct contact of a sensing apparatus with the biological system; methods which extract samples from the biological system by invasive, minimally invasive, and non-invasive sampling techniques, wherein the sensing apparatus is contacted with the extracted sample; methods which rely on indirect contact of a sensing apparatus with the biological system; and the like. In preferred embodiments of the invention, methods are used to extract samples from the biological sample using minimally invasive or non-invasive sampling techniques. The sensing apparatus used with any of the above-noted methods can employ any suitable sensing element to provide the raw signal including, but not limited to, physical, chemical, electrochemical, photochemical, spectrophotometric, polarimetric, calorimetric, radiometric, or like elements. In preferred embodiments of the invention, a biosensor is used which comprises an electrochemical sensing element.
In one particular embodiment of the invention, the raw signal is obtained using a transdermal sampling system that is placed in operative contact with a skin or mucosal surface of the biological system. The sampling system transdermally extracts the analyte from the biological system using any appropriate sampling technique, for example, iontophoresis. The transdermal sampling system is maintained in operative contact with the skin or mucosal surface of the biological system to provide for such continual or continuous analyte measurement.
The analyte can be any specific substance or component that one is desirous of detecting and/or measuring in a chemical, physical, enzymatic, or optical analysis. Such analytes include, but are not limited to, amino acids, enzyme substrates or products indicating a disease state or condition, other markers of disease states or conditions, drugs of abuse, therapeutic and/or pharmacologic agents, electrolytes, physiological analytes of interest (e.g., calcium, potassium, sodium, chloride, bicarbonate (CO2), glucose, urea (blood urea nitrogen), lactate, hematocrit, and hemoglobin), lipids, and the like. In preferred embodiments, the analyte is a physiological analyte of interest, for example glucose, or a chemical that has a physiological action, for example a drug or pharmacological agent.
Accordingly, it is an object of the invention to provide a method for continually or continuously measuring an analyte present in a biological system, wherein raw signals are obtained from a suitable sensing apparatus, and then subjected to signal processing techniques. More particularly, the raw signals undergo a data screening method in order to eliminate outlier signals and/or poor (incorrect) signals using a predefined set of selection criteria. In addition, or alternatively, the raw signal can be converted in a conversion step which (i) removes or corrects for background information, (ii) integrates the raw signal over a sensing time period, (iii) performs any process which converts the raw signal from one signal type to another, or (iv) performs any combination of steps (i), (ii) and/or (iii). In preferred embodiments, the conversion step entails a baseline background subtraction method to remove background from the raw signal and an integration step. In other embodiments, the conversion step can be tailored for use with a sensing device that provides both active and reference (blank) signals; wherein mathematical transformations are used to individually smooth active and reference signals, and/or to subtract a weighted reference (blank) signal from the active signal. In still further embodiments, the conversion step includes correction functions which account for changing conditions in the biological system and/or the biosensor system (e.g., temperature fluctuations in the biological system, temperature fluctuations in the sensor element, skin conductivity fluctuations, or combinations thereof). The result of the conversion step is an initial signal output which provides a value which can be correlated with the concentration of the target analyte in the biological sample.
It is also an object of the invention to provide a signal processing calibration step, wherein the raw or initial signals obtained as described above are converted into an analyte-specific value of known units to provide an interpretation of the signal obtained from the sensing device. The interpretation uses a mathematical transformation to model the relationship between a measured response in the sensing device and a corresponding analyte-specific value. Such mathematical transformations can entail the use of linear or nonlinear regressions, or neural network algorithms. In one embodiment, the calibration step entails calibrating the sensing device using a single- or multi-point calibration, and then converting post-calibration data using correlation factors, time corrections and constants to obtain an analyte-specific value. Further signal processing can be used to refine the information obtained in the calibration step, for example, where a signal processing step is used to correct for signal differences due to variable conditions unique to the sensor element used to obtain the raw signal. In one embodiment, this further step is used to correct for signal time-dependence, particularly signal decline. In another embodiment, a constant offset term is obtained, which offset is added to the signal to account for a non-zero signal at an estimated zero analyte concentration.
Further, the methods of the present invention include enhancement of skin permeability by pricking the skin with micro-needles. In addition, the sampling system can be programed to begin execution of sampling and sensing at a defined time(s).
It is yet a further object of the invention to provide a monitoring system for continually or continuously measuring an analyte present in a biological system. The monitoring system comprises, in operative combination: (a) a sampling means for continually or continuously extracting the analyte from the biological system, (b) a sensing means in operative contact with the analyte extracted by the sampling means, and (c) a microprocessor means in operative communication with the sensing means. The sampling means is adapted for extracting the analyte across a skin or mucosal surface of a biological system. The sensing means is used to obtain a raw signal from the extracted analyte, wherein the raw signal is specifically related to the analyte. The microprocessor means is used to subject the raw signal to a conversion step, thereby converting the same into an initial signal output which is indicative of the amount of analyte extracted by the sampling means, and then perform a calibration step which correlates the initial signal output with a measurement value indicative of the concentration of analyte present in the biological system at the time of extraction. In one embodiment, the monitoring system uses iontophoresis to extract the analyte from the biological system. In other embodiments, the monitoring system is used to extract a glucose analyte from the biological system. Further, the microprocessor can be programed to begin execution of sampling and sensing at a defined time(s).
Additional objects, advantages and novel features of the invention will be set forth in part in the description which follows, and in part will become apparent to those skilled in the art upon examination of the following, or may be learned by practice of the invention.